Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways

Background Neutrophilic asthma (NA) is associated with increased airway interleukin (IL)-17 and abnormal bacterial community such as dominance of nontypeable Haemophilus influenzae (NTHi), particularly during asthma exacerbations. Bacteria release various products including DNA, but whether they cooperate with IL-17 in exaggerating neutrophilic inflammation is unclear. We sought to investigate the role of bacteria-derived DNA in airway neutrophilic inflammation related to IL-17-high asthma and underlying mechanisms (e.g. Toll-like receptor 9 (TLR9)/IL-36 gamma signalling axis). Methods Bacterial DNA, IL-8 and IL-36 gamma were measured in bronchoalveolar lavage fluid (BALF) of people with asthma and healthy subjects. The role of co-exposure to IL-17 and bacterial DNA or live bacteria in neutrophilic inflammation, and the contribution of the TLR9/IL-36 gamma signalling axis, were determined in cultured primary human airway epithelial cells and alveolar macrophages, and mouse models. Results Bacterial DNA levels were increased in asthma BALF, which positively correlated with IL-8 and neutrophil levels. Moreover, IL-36 gamma increased in BALF of NA patients. Bacterial DNA or NTHi infection under an IL-17-high setting amplified IL-8 production and mouse lung neutrophilic inflammation. DNase I treatment in IL-17-exposed and NTHi-infected mouse lungs reduced neutrophilic inflammation. Mechanistically, bacterial DNA-mediated amplification of neutrophilic inflammation is in part dependent on the TLR9/IL-36 gamma signalling axis. Conclusions Bacterial DNA amplifies airway neutrophilic inflammation in an IL-17-high setting partly through the TLR9 and IL-36 gamma signalling axis. Our novel findings may offer several potential therapeutic targets including TLR9 antagonists, IL-36 gamma neutralising antibodies and DNase I to reduce asthma severity associated with exaggerated airway neutrophilic inflammation.

Automated summary

This study found that bacterial DNA levels were increased in the bronchoalveolar lavage fluid (BALF) of patients with neutrophilic asthma (NA), and were positively correlated with IL-8 and neutrophil levels. Additionally, IL-36γ levels were also increased. Bacterial DNA amplified neutrophilic inflammation in an IL-17-high setting through the TLR9 and IL-36γ signalling axis.